tbuckley/cabot-search huggingface dataset:
Abstract 1069: OBT076, a clinical-stage ADC, displays synergy with oxaliplatin and cisplatin in preclinical gastric cancer models
Authors: Arnima Bisht, Murray Cox, Chander Sekhar Peddaboina, Michael Crocamo, Abderrahim Fandi, Christian Rohlff
Journal: Cancer Research (2022)

Abstract CD205 is a transmembrane glycoprotein, robustly expressed in malignancies from varied histotypes, making it an ideal target for Antibody Drug Conjugate (ADC) therapy. OBT076 is a novel and selective clinical stage ADC with potent activity against CD205-positive liquid and solid tumors. We explored the cellular cytotoxicity profile of combination chemotherapy with OBT076 and two standard-of-care platinum-based compounds, Oxaliplatin (Ox) and Cisplatin (Cis), in preclinical gastric, pancreatic and colorectal cancer models. A panel of gastric cancer and other solid tumor cell lines were selected, based on mRNA data, for CD205 expression. This was confirmed using flow cytometry. The cell lines were assessed for susceptibility to monotherapy with OBT076, Ox and Cis. Cells lines displaying positive cytotoxic responses were assessed for susceptibility to combination chemotherapy by first treating cells with a single dose of OBT076 for 72 hours, leading to 20% growth inhibition (IC20), and subsequently with either Ox or Cis for 48 hours (OBT-Ox and OBT-CIS, respectively). The ATP-dependent fluorescence-based cellular viability system cell titer-glo was used as the cytotoxic readout. In our preclinical gastric cancer model, pre-treatment with OBT076 followed by either Ox or Cis displayed synergistic combination effects, reducing the half-maximal inhibitory concentration (IC50) of Ox and Cis by 40- and 10-fold respectively. The resultant cellular cytotoxicity of OBT-Ox and OBT-Cis combination therapy was higher compared to monotherapy with either agent. Moreover, while monotherapy with Ox was less potent than with Cis, OBT-Ox achieved similar potency to OBT076-Cis. For colorectal and pancreatic cancer models, the effects were less pronounced: OBT076-combination therapy increased Platinum sensitivity by 2 to 5 times. No synergistic effects were observed when the treatment order was reversed. These results and those from ongoing in vivo studies in gastric cancer models will be discussed. In summary OBT076, a clinical stage ADC displays synergistic anti-tumor effects in preclinical gastric cancer models, when used in combination with Ox or Cis. OBT076 is currently being evaluated in the gastric clinical population where Platinum-based therapies remain the mainstay of treatment. Citation Format: Arnima Bisht, Murray Cox, Chander Sekhar Peddaboina, Michael Crocamo, Abderrahim Fandi, Christian Rohlff. OBT076, a clinical-stage ADC, displays synergy with oxaliplatin and cisplatin in preclinical gastric cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1069.
Abstract 5346: WAVE3 phosphorylation promotes chemoresistance and cancer stemness in triple negative breast cancer through downstream of β-catenin oncogenic signaling
Authors: Wei Wang, Priyanka Rana, Akram Alkrekshi, Vesna Markovic, Khalid Sossey-Alaoui
Journal: Cancer Research (2022)

Abstract Acquisition of the metastatic phenotype is responsible for the death of ~90% of breast cancer (BC) patients. Metastatic BC is the 2nd leading cause of cancer-related deaths in women in the United States, annually accounting for more than 40,100 deaths and 266,000 new cases of invasive BC. Amongst individual BC subtypes, those classified as TNBCs are especially lethal due to their highly metastatic behavior and propensity to recur rapidly. As a group, TNBCs lack expression of hormone receptors (ER-α and PR) and ErbB2/HER2, which has prevented the development of FDA-approved targeted drug therapies that are effective against this BC subtype. Likewise, recurrent TNBCs frequently acquire resistance to standard-of-care chemotherapeutic agents (e.g., doxorubicin, cyclophosphamides, and taxanes) through mechanisms that remain incompletely understood. We established Wiskott-Aldrich Syndrome Protein-3 (WAVE3) as a novel promoter of TNBC development and metastatic progression. Our recently published studies have shown that WAVE3 phosphorylation regulates the interplay between PI3K, TGF-β, and EGF signaling pathways. In this study, we show that WAVE3 phosphorylation promotes chemotherapy-resistance and cancer stemness in TNBC, both in vitro and in in vivo mouse models. CRISPR/Cas9-mediated inactivation of WAVE3 resulted in inhibition of 2D growth and 3D tumorspheres’ invasion of TNBC cells in vitro, as well as tumor growth and metastasis in vivo. In addition, while re-expression of phospho-active WAVE3 in the WAVE3-deficient TNBC cells restored the oncogenic activity of WAVE3, re-expression of phospho-mutant WAVE3 or the pharmacologic inhibition of WAVE3 phosphorylation did not. Further studies revealed that dual blocking WAVE3 expression or phosphorylation with chemotherapy treatment inhibited the activity and expression of β-catenin. Importantly, a combination of WAVE3-deficiency and chemotherapy suppressed the oncogenic behavior of chemo-resistant TNBC cells, both in vitro and in vivo. This study suggests that a targeted therapeutic strategy against WAVE3 could be effective for the treatment of chemoresistant TNBC tumors. Citation Format: Wei Wang, Priyanka Rana, Akram Alkrekshi, Vesna Markovic, Khalid Sossey-Alaoui. WAVE3 phosphorylation promotes chemoresistance and cancer stemness in triple negative breast cancer through downstream of β-catenin oncogenic signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5346.
Abstract 5167: Enhanced isolation of circulating tumor cells from leukapheresis material enabled by Akadeum microbubbles
Authors: Edward Grimley, Jon Roussey, Chia Ku, Carolina Livi, Nadia Petlakh-Co, Casey Wegner, Brandon H. McNaughton
Journal: Cancer Research (2022)

Abstract Circulating tumor cells (CTCs) have shown incredible promise in clinical and diagnostic applications. CTC-based liquid biopsies can aid in earlier diagnosis, identify the stage of disease, guide therapeutic aggressiveness, and be used to monitor response to treatment. While CTCs hold incredible promise in these areas, there are inherent limitations that hinder realization of the full potential of CTC-based liquid biopsy tests. The rarity of CTCs is one of the most significant factors limiting clinical utility. A standard 10-mL blood draw may simply not contain the number of CTCs needed to yield meaningful results. One method to analyze greater blood volume is by leukapheresis. While clinical leukapheresis can enrich mononuclear cells, including CTCs, from almost the entire volume of a patient’s blood, most downstream CTC enrichment methods are not compatible with leukapheresis material as a starting sample. To overcome these compatibility issues, Akadeum Life Sciences has developed a novel and proprietary Buoyancy Activated Cell Sorting (BACS™) microbubble platform that can be functionalized to selectively enrich biological samples for target cell populations using a fast, easy protocol that is exceptionally gentle on delicate cells of interest. Akadeum’s low-density BACS microbubbles are mixed into the sample where they quickly engage their targets and naturally float them to the surface for removal. This straightforward approach is elegant in simplicity and powerful in application, offering some of the fastest and most gentle isolations available. In this study, we demonstrate a protocol for the depletion of white blood cells (WBCs) &amp; residual red blood cells (RBCs) from leukapheresis material via microbubbles. This novel protocol reveals a &amp;gt; 99% combined depletion of residual RBCs and WBCs, providing over 120-fold enrichment of tumor cells. Importantly, this protocol delivers exceptional yield with &amp;gt; 99% retention of the target tumor cells. This optimized workflow delivers an enriched and viable population of untouched and unaltered CTCs for downstream use. Citation Format: Edward Grimley, Jon Roussey, Chia Ku, Carolina Livi, Nadia Petlakh-Co, Casey Wegner, Brandon H. McNaughton. Enhanced isolation of circulating tumor cells from leukapheresis material enabled by Akadeum microbubbles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5167.
Abstract 882: A novel p73 C-terminal isoform, p73α1, regulates inflammation and tumor suppression via the Notch1 pathway
Authors: Kyra Laubach, Wenshen Yan, Xiangmudong Kong, Mingyi Chen, Jin Zhang, Xinbin Chen
Journal: Cancer Research (2022)

Abstract p73, a member of the p53 family, is expressed as two N-terminal isoforms: TA, a tumor suppressor and ΔN, an oncoprotein. Alternative RNA splicing at the 3` end gives rise to multiple C-terminal isoforms, but their function is largely unknown. To address this, CRISPR was used to knock out exon 12 (E12) in several cell lines and mice, leading to isoform switching from p73α to p73α1. p73α1 is a novel isoform whose expression we detected in multiple cancer cell lines. We found that knockout of E12 inhibits the cell proliferation and migration abilities of H1299 and MIA PaCa-2 cancer cells and E12-/- MEFs exhibit increased cellular senescence. Similarly, ectopic expression of p73α1 in H1299 cells suppresses cell proliferation and knockdown of p73α1 restores the cell proliferative and migratory capacities of H1299 E12-/- cells. Consistently, we found that E12+/- mice are not prone to spontaneous tumors, unlike Trp73+/- mice, but instead are prone to chronic systemic inflammation and show elevated IL-1β and IL-6 expression in inflamed tissues. We then identified Notch1, a master regulator of the inflammatory response, as a mediator of p73α1-induced inflammation and tumor suppression, and found it to be elevated in inflamed E12+/- mouse tissues. Furthermore, we found that knockdown of Notch1 enhances cell proliferation and migration in H1299 E12-/- cells. Together, these data suggest that p73α1 plays a role in the inflammatory response and tumor suppression via Notch1. Citation Format: Kyra Laubach, Wenshen Yan, Xiangmudong Kong, Mingyi Chen, Jin Zhang, Xinbin Chen. A novel p73 C-terminal isoform, p73α1, regulates inflammation and tumor suppression via the Notch1 pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 882.
Addressing the routine failure to clinically identify monogenic cases of common disease
Authors: Michael F. Murray, Muin J. Khoury, Noura S. Abul-Husn
Journal: Genome Medicine (2022)

Abstract Changes in medical practice are needed to improve the diagnosis of monogenic forms of selected common diseases. This article seeks to focus attention on the need for universal genetic testing in common diseases for which the recommended clinical management of patients with specific monogenic forms of disease diverges from standard management and has evidence for improved outcomes. We review evidence from genomic screening of large patient cohorts, which has confirmed that important monogenic case identification failures are commonplace in routine clinical care. These case identification failures constitute diagnostic misattributions , where the care of individuals with monogenic disease defaults to the treatment plan offered to those with polygenic or non-genetic forms of the disease. The number of identifiable and actionable monogenic forms of common diseases is increasing with time. Here, we provide six examples of common diseases for which universal genetic test implementation would drive improved care. We examine the evidence to support genetic testing for common diseases, and discuss barriers to widespread implementation. Finally, we propose recommendations for changes to genetic testing and care delivery aimed at reducing diagnostic misattributions, to serve as a starting point for further evaluation and development of evidence-based guidelines for implementation.
Abstract 2443: Knocking out <i>SNCA</i> in SKMEL28 melanoma cells suppresses EMT and prevents invasion
Authors: Nithya Gajendran, Santhanasabapathy Rajasekaran, Nirjhar M. Aloy, Sahar Shekoohi, Stephan N. Witt
Journal: Cancer Research (2022)

Abstract Malignant melanoma is one of the most aggressive and fifth most prevalent cancer among men and women. Clinical and epidemiological studies shows that Parkinson’s disease (PD) patients have higher risk of developing invasive melanoma, and, reciprocally, patients with invasive melanoma have a higher risk of developing PD. Alpha-synuclein (α-syn; SNCA), an intrinsically disordered protein expressed in neurons, is also highly expressed in malignant melanoma and is a common molecular signature between Parkinson’s disease and melanoma. We have previously reported that SK-Mel-28 SNCA-knockout (KO) cells exhibit suppressed tumor growth and proliferation in vivo and in vitro, and that putting back SNCA via lenti virus restored the phenotype to that of the control cells. The present study is designed to investigate the role of α-syn in melanoma progression in SK-MEL-28 cells in the context of metastasis and the epithelial-to-mesenchymal transition (EMT). The SK-Mel-28 SNCA-KO clones showed a significant decrease in the cell-surface protein L1CAM, a major cell adhesion molecule highly expressed in various melanoma and correlates with melanoma progression, whereas the knock in clones resembled the control. Migration and invasion assay were performed using transwell chambers showed a profound migratory and invasive defect in SNCA-KO clones. To explore further whether this is a proliferative or migratory defect, a single cell phagokinetic motility assay was performed with colloidal gold which showed a marked decrease in cell motility in knockout clones compared to control and knock in clones, which was consistent with our migration and invasion experiments. To determine the proteins involved in the inhibition of invasion mediated by α-syn, we immunoblotted for the mesenchymal markers N-cadherin and vimentin, and these were significantly downregulated in the SNCA-KO clones. These data reinforce that knocking out SNCA impedes melanoma cell migration and invasion in SK-Mel- 28 cell line, implying that α-syn might be a novel therapeutic target for malignant melanoma. Citation Format: Nithya Gajendran, Santhanasabapathy Rajasekaran, Nirjhar M. Aloy, Sahar Shekoohi, Stephan N. Witt. Knocking out SNCA in SKMEL28 melanoma cells suppresses EMT and prevents invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2443.
Abstract 5971: DEPDC1B promotes melanoma angiogenesis and metastasis through sequestration of ubiquitin ligase CDC16 to stabilize secreted SCUBE3
Authors: Feng Hu, Ki On Fong, May P.L Cheung, Jessica A.J Liu, Rui Liang, Tsz Wai Li, Rakesh Sharma, Philip P.C Ip, Xintao Yang, Martin Cheung
Journal: Cancer Research (2022)

Abstract The ability of melanoma to acquire metastasis through the induction of angiogenesis is one of the major causes of skin cancer death. Here, we find that high transcript levels of DEPDC1B in cutaneous melanomas are significantly associated with a poor prognosis. Tissue microarray analysis indicates DEPDC1B expression is positively correlated with SOX10 in the different stages of melanoma. Consistently, DEPDC1B is both required and sufficient for melanoma growth, metastasis, angiogenesis, and functions as a direct downstream target of SOX10 to partly mediate its oncogenic activity. In contrast to other tumor types, the DEPDC1B-mediated enhancement of melanoma metastatic potential is not dependent on the activities of RHO GTPase signaling and canonical Wnt signaling, but is acquired through secretion of SCUBE3, which is crucial for promoting angiogenesis in vitro and in vivo. Mechanistically, DEPDC1B regulates SCUBE3 protein stability through the competitive association with ubiquitin ligase CDC16 to prevent SCUBE3 from undergoing degradation via the ubiquitin-proteasome pathway. Importantly, expression of SOX10, DEPDC1B, and SCUBE3 are positively correlated with microvessel density in the advanced stage of melanomas. In conclusion, we reveal a SOX10-DEPDC1B-SCUBE3 regulatory axis promotes melanoma angiogenesis and metastasis, which suggests targeting secreted SCUBE3 can be a therapeutic strategy against metastatic melanoma. Citation Format: Feng Hu, Ki On Fong, May P.L Cheung, Jessica A.J Liu, Rui Liang, Tsz Wai Li, Rakesh Sharma, Philip P.C Ip, Xintao Yang, Martin Cheung. DEPDC1B promotes melanoma angiogenesis and metastasis through sequestration of ubiquitin ligase CDC16 to stabilize secreted SCUBE3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5971.
Distinct stromal and immune cell interactions shape the pathogenesis of rheumatoid and psoriatic arthritis
Authors: Achilleas Floudas, Conor M Smith, Orla Tynan, Nuno Neto, Vinod Krishna, Sarah M Wade, Megan Hanlon, Clare Cunningham, Viviana Marzaioli, Mary Canavan, Jean M Fletcher, Ronan H Mullan, Suzanne Cole, Ling-Yang Hao, Michael G Monaghan, Sunil Nagpal, Douglas J Veale, Ursula Fearon
Journal: Annals of the Rheumatic Diseases (2022)

Objectives Immune and stromal cell communication is central in the pathogenesis of rheumatoid arthritis (RA) and psoriatic arthritis (PsA), however, the nature of these interactions in the synovial pathology of the two pathotypes can differ. Identifying immune-stromal cell crosstalk at the site of inflammation in RA and PsA is challenging. This study creates the first global transcriptomic analysis of the RA and PsA inflamed joint and investigates immune-stromal cell interactions in the pathogenesis of synovial inflammation. Methods Single cell transcriptomic profiling of 178 000 synovial tissue cells from five patients with PsA and four patients with RA, importantly, without prior sorting of immune and stromal cells. This approach enabled the transcriptomic analysis of the intact synovial tissue and identification of immune and stromal cell interactions. State of the art data integration and annotation techniques identified and characterised 18 stromal and 14 immune cell clusters. Results Global transcriptomic analysis of synovial cell subsets identifies actively proliferating synovial T cells and indicates that due to differential λ and κ immunoglobulin light chain usage, synovial plasma cells are potentially not derived from the local memory B cell pool. Importantly, we report distinct fibroblast and endothelial cell transcriptomes indicating abundant subpopulations in RA and PsA characterised by differential transcription factor usage. Using receptor–ligand interactions and downstream target characterisation, we identify RA-specific synovial T cell-derived transforming growth factor (TGF)-β and macrophage interleukin (IL)-1β synergy in driving the transcriptional profile of FAPα + THY1 + invasive synovial fibroblasts, expanded in RA compared with PsA. In vitro characterisation of patient with RA synovial fibroblasts showed metabolic switch to glycolysis, increased adhesion intercellular adhesion molecules 1 expression and IL-6 secretion in response to combined TGF-β and IL-1β treatment. Disrupting specific immune and stromal cell interactions offers novel opportunities for targeted therapeutic intervention in RA and PsA.
Abstract 5531: PD-1 blockades plus targeted therapy and cytotoxic drugs as conversion therapy in unresectable metastatic colorectal cancer (mCRC): A real-world experience
Authors: Ling Huang, Liying Zhao, Xinyi Liu, Mengli Huang
Journal: Cancer Research (2022)

Abstract Background: Resection of metastatic tumor site has been proven beneficial for survival in mCRC, thus the need for conversion therapy of mCRC is strong. Anti-PD-1 antibody has presented durable clinical response in mismatch repair deficient (dMMR)/microsatellite instable (MSI-H) mCRC as first-line treatment while its efficacy in microsatellite stable (MSS) mCRC is still controversial. Combination of anti-PD-1 and targeted therapy or chemotherapies was regarded as potential regimens in MSS mCRC. Moreover, it is fully elucidated that immune checkpoint inhibitor used in initial therapy would have higher probability to achieve treatment response. We retrospectively analyzed the efficacy of anti-PD-1 plus targeted drugs and cytotoxic drugs as conversion/first-line therapy in fifteen untreated mCRC. Methods: Thirteen MSS and two MSI-H mCRC were included. All patients received at least one cycle of anti-PD-1 (Pembrolizumab, Sintilimab or Toripalimab, q3w) combined with bevacizumab or cetuximab plus chemotherapy (FOLFOX or FOLFOXIRI regimens). Results: 8 patients were RAS-mutant and 1 patient harbored BRAF-V600E. 13 patients had liver metastasis, 3 had lung metastasis and 3 had retroperitoneal lymph metastasis. 4 patients, including 2 MSI-H patients and 2 MSS patients had complete response (CR), 8 patients had partial response (PR), 2 patients had stable disease (SD) and 1 patient had progression disease (PD). The conversion rate was 80% (12/15), including 10 patients received resection or thermal ablation of metastatic tumor and 2 patients achieved CR. 9 patients were R0 resection and 10 patients achieved NED (no evidence of disease) status. G3-4 treatment-related adverse events (AEs) occurred in 1 patient (neutropenia, n=1). No patient discontinued treatment due to adverse events. Conclusions: The triplet regimen of anti-PD-1, bevacizumab or cetuximab and chemotherapy was safe and tolerant and showed encouraging anti-tumor activities in MSS mCRC. Our experience suggested the clinical value of PD-1 blockades as initial treatment in MSS mCRC. Citation Format: Ling Huang, Liying Zhao, Xinyi Liu, Mengli Huang. PD-1 blockades plus targeted therapy and cytotoxic drugs as conversion therapy in unresectable metastatic colorectal cancer (mCRC): A real-world experience [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5531.
Saline-infused radiofrequency ablation: A review on the key factors for a safe and reliable tumour treatment
Authors: Antony S. K. Kho, Ean H. Ooi, Ji J. Foo, Ean T. Ooi
Journal: IEEE Reviews in Biomedical Engineering (2022)

Radiofrequency ablation (RFA) combined with saline infusion into tissue is a promising technique to ablate larger tumours. Nevertheless, the application of saline-infused RFA remains at clinical trials due to the contradictory findings as a result of the inconsistencies in experimental procedures. These inconsistencies not only magnify the number of factors to consider during the treatment, but also obscure the understanding of the role of saline in enlarging the coagulation zone. Consequently, this can result in major complications, which includes unwanted thermal damages to adjacent tissues and also incomplete ablation of the tumour. This review aims to identify the key factors of saline responsible for enlarging the coagulation zone during saline-infused RFA, and provide a proper understanding on their effects that is supported with findings from computational studies to ensure a safe and reliable cancer treatment.